The cancer stem cell hypothesis posits that similar to normal tissue, a distinct subset of specialized cells has the capacity to self-renew and continuously populates the tumor. Cancer stem cells (CSCs) are implicated in tumor initiation, progression, metastasis and relapse making them desirable targets for therapeutic intervention.
One of the most well-characterized tissue stem cell populations is the leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5) crypt cells in the gastrointestinal tract which give rise to all the differentiated cell types within the homeostatic intestinal epithelia. LgR5 is a seven-transmembrane protein found on the surface of actively cycling intestinal stem cells (ISCs). Human LgR5 is a 907 amino acid protein, of which ˜540 amino acids are predicted to be in the extracellular space following cleavage of the amino-terminal signal sequence. LgR5 comprises 17 imperfect leucine-rich repeat motifs in the ectodomain, and a cysteine-rich region located between the leucine-rich repeats and the first transmembrane domain.
LgR5-expressing ISCs are sensitive to Wnt modulation and are primarily responsible for homeostatic regeneration of the intestinal epithelium. Elimination of LgR5-expressing cells in mice does not affect homeostasis of intestinal epithelium, however, suggesting that other cell types can compensate for loss of this cell population. Tian et al., Nature 478: 255-259 (2011). R-spondins enhance WNT signaling by WNT3A, and all four R-spondins, RSPO1, RSPO2, RSPO3, and RSPO4, are able to bind to LgR5. Lau et al., Nature 476: 293-297 (2011).
LgR5+ cells are proposed also to serve as the cells of origin for intestinal cancers and act as CSCs suggesting that elimination of the LgR5+ cells could have a profound impact on tumor growth and maintenance.
Lineage tracing of APC mutant tumors from LgR5+ cells demonstrates that multiple cell types in intestinal tumors are derived from an LgR5+ progenitor. Moreover LgR5+ cells are proposed to initiate and continuously contribute progeny to the tumor mass, suggesting that elimination of the LgR5+ cells could have a profound impact on tumor growth and maintenance. However, a long-standing issue in determining the expression of LgR5 has been the lack of a quality Immunohistochemistry (IHC) reactive antibody.
There is a need in the art for agents that target LgR5 for the diagnosis and treatment of LgR5-associated conditions, such as cancer. The invention fulfills that need and provides other benefits.